CPEPA-UGC Centre for "Electro-physiological and Neuro-imaging studies including Mathematical Modelling", University of Calcutta, Kolkata, West Bengal, India; Department of Physiology, University of Calcutta, Kolkata, West Bengal, India.
Department of Physiology, Vidyasagar College, Kolkata, West Bengal, India.
Life Sci. 2020 Sep 15;257:118096. doi: 10.1016/j.lfs.2020.118096. Epub 2020 Jul 15.
The molecular pathogenesis of COVID-19 is similar to other coronavirus (CoV) infections viz. severe acute respiratory syndrome (SARS) in human. Due to scarcity of the suitable treatment strategy, the present study was undertaken to explore host protein(s) targeted by potent repurposed drug(s) in COVID-19.
The differentially expressed genes (DEGs) were identified from microarray data repository of SARS-CoV patient blood. The repurposed drugs for COVID-19 were selected from available literature. Using DEGs and drugs, the protein-protein interaction (PPI) and chemo-protein interaction (CPI) networks were constructed and combined to develop an interactome model of PPI-CPI network. The top-ranked sub-network with its hub-bottleneck nodes were evaluated with their functional annotations.
A total of 120 DEGs and 65 drugs were identified. The PPI-CPI network (118 nodes and 293 edges) exhibited a top-ranked sub-network (35 nodes and 174 connectivities) with 12 hub-bottleneck nodes having two drugs chloroquine and melatonin in association with 10 proteins corresponding to six upregulated and four downregulated genes. Two drugs interacted directly with the hub-bottleneck node i.e. matrix metallopeptidase 9 (MMP9), a host protein corresponding to its upregulated gene. MMP9 showed functional annotations associated with neutrophil mediated immunoinflammation. Moreover, literature survey revealed that angiotensin converting enzyme 2, a membrane receptor of SARS-CoV-2 virus, might have functional cooperativity with MMP9 and a possible interaction with both drugs.
The present study reveals that between chloroquine and melatonin, melatonin appears to be more promising repurposed drug against MMP9 for better immunocompromisation in COVID-19.
COVID-19 的分子发病机制与其他冠状病毒（CoV）感染相似，例如人类的严重急性呼吸综合征（SARS）。由于缺乏合适的治疗策略，本研究旨在探索针对 COVID-19 的潜在再利用药物靶向的宿主蛋白。
从 SARS-CoV 患者血液的微阵列数据存储库中鉴定差异表达基因（DEGs）。从现有文献中选择用于 COVID-19 的再利用药物。使用 DEGs 和药物构建蛋白质-蛋白质相互作用（PPI）和化学蛋白质相互作用（CPI）网络，并将其组合以开发 PPI-CPI 网络的互作体模型。评估具有功能注释的排名靠前的子网络及其枢纽瓶颈节点。
共鉴定出 120 个 DEGs 和 65 种药物。PPI-CPI 网络（118 个节点和 293 个边）显示出排名靠前的子网络（35 个节点和 174 个连接），其中包含 12 个枢纽瓶颈节点，有两种药物氯喹和褪黑素与 10 种对应于六个上调和四个下调基因的蛋白质相关联。两种药物与枢纽瓶颈节点即基质金属蛋白酶 9（MMP9）直接相互作用，MMP9 对应其上调基因的宿主蛋白。MMP9 显示与中性粒细胞介导的免疫炎症相关的功能注释。此外，文献调查显示，SARS-CoV-2 病毒的膜受体血管紧张素转换酶 2 可能与 MMP9 具有功能协同作用，并且可能与两种药物相互作用。
本研究表明，在氯喹和褪黑素之间，褪黑素似乎是针对 MMP9 的更有前途的再利用药物，可在 COVID-19 中实现更好的免疫抑制作用。
